Interleukin-5 (IL-5) is a hematopoietic cytokine that specifically promotes the differentiation, survival and function of eosinophils, and is considered central to the pathophysiology of eosinophilic inflammation in allergic disorders and asthma. The IL-5 receptor (IL-5R) is a heterodimer consisting of an IL-5 specific alpha chain (IL-5Ralpha) and a common beta chain (betac) which alone does not bind IL-5, but is necessary for agonistic signal transduction and is shared with the IL-3Ralpha and GM-CSFRalpha for signaling. The overall goal of this proposal is to understand the mechanisms that regulate IL-5 signaling through the ac subunit of the IL-5R. Our previous studies delineated the functional structure of IL-5 and the binding domains within IL-5 that engage the IL-5Ralpha and betac receptor subunits. Our preliminary studies for this competitive renewal suggest that IL-5 signaling through the ac may be dependent on a conformational charge field surrounding the glu 13 residue of IL-5. Furthermore, we made the novel finding that IL-5 agonistic ligation of the IL-5R also initiates proteasome termination of IL-5 signaling that results in both homotypic and heterotypic desensitization of cells to each of the ac engaging cytokines, IL-3, IL-5, and GM-CSF. Specific aims of this project are to: 1) Determine the residues in IL-5 that are required for functional ligation of ac; 2) Determine the molecular mechanisms that regulate proteasome termination of signaling by ac; 3) Investigate the potential for proteasome-mediated heterotypic desensitization of ac to modulate the terminal differentiation and function of IL-5 responsive cells; and 4) Explore the potential for proteasome degradation of shared cytokine receptor subunits to be a conserved physiologic mechanism for both homolypic and heterotypic desensitization of cytokine signaling.